https://seekingalpha.com/news/3846043-mereo-biopharma-falls-as-price-target-lowered-to-5-at-needham
Monday, June 6, 2022
Asco 2022 – investors clutch at the Tigit straws
Tigit blockade, already facing existential questions after the failure of Roche’s tiragolumab in non-small cell lung cancer, took another hit today. A late-breaker at Asco has laid bare the unmitigated disaster of tiragolumab’s other flop, in the more intractable small-cell lung cancer setting.
Just how bad is it? In Skyscraper-02, the SCLC trial, adding tiragolumab to Tecentriq actually worsened progression-free survival numerically. However, a key disclosure about Skyskraper-02’s statistical analysis plan has raised hopes that Skyscraper-01, the failed NSCLC study, might not be dead and buried just yet.
How this pans out is crucial not only for Roche, which has invested hugely in Tigit, but for numerous smaller biotechs working on this mechanism who had been hoping for some crumbs of comfort from Skyscraper-02. Where stocks like Iteos, Compugen, Arcus and Mereo open tomorrow will be telling.
Apportioning alpha
Importantly, nothing has been revealed about Skyscraper-01, the front-line NSCLC study, beyond its miss at interim analysis on PFS and a numerical trend favouring an OS benefit. That trial tests tiragolumab plus Tecentriq versus Tecentriq alone in PD-L1 ≥50% expressers.
The central question is what the numerical PFS miss looks like, and how Roche has divided up statistical power in Skyscraper-01. The standard of statistical significance at p=0.05 is typically split for multiple analyses across multiple endpoints.
Indeed, Evaluate Vantage understands that whisper numbers among optimistic investors are that Skyscraper-01’s PFS result has yielded a p value well below 0.05, but that this nevertheless missed statistical significance, which had been set at a much more aggressive level.
Even more important is how much statistical power remains to show an OS benefit at a subsequent interim analysis. As far as PFS goes, of course, whatever powering – or “alpha” – was apportioned to this endpoint at first interim has been spent.
So why do today’s Skyscraper-02 data add optimism? The key is this SCLC study’s statistical design, posted at today’s Asco late-breaker by Memorial Sloan Kettering’s Dr Charles Rudin. Revealingly, almost the entirety of the alpha at p=0.05 was assigned to OS, meaning that a very tough p value of 0.001 needed to be cleared to declare a statistical win on PFS.
Source: Dr Charles Rudin & Asco.
No one is suggesting that Skyscraper-01 has an identical statistical design. And clearly there is no salvaging anything from tiragolumab’s SCLC study, which was a flop on all counts.
But it is nevertheless possible that Roche has apportioned the majority of the alpha in Skyscraper-01 to OS. In a note to clients Evercore ISI’s Umer Raffat wrote today: “These tidbits raise our confidence that there is a real chance Roche can hit on a subsequent OS analysis of Skyscaper-01 in NSCLC; next interim [due] possibly later in the year.”
Therapeutically irrelevant?
As for Skyscraper-02, there was no attempt by Dr Rudin to gloss over the disaster. Perhaps damningly for Merck & Co, he stated: “Targeting Tigit in SCLC does not appear to be therapeutically relevant.”
Merck had started Keyvibe-008, a broadly similar front-line SCLC trial with its Tigit MAb vibostolimab plus Keytruda, at precisely the same time that Skyscraper-02 was toplined as a flop. However, speaking to Evaluate Vantage Eric Rubin, Merck’s senior vice-president of early-stage oncology, said: “Roche’s failure isn’t going to detract from our interest in [vibostolimab].”
Of more importance will be Merck’s work in NSCLC, where the Keyvibe-003 vibostolimab plus Keytruda trial is ongoing. Mr Rubin drew a distinction between Skyscraper-01 and Keyvibe-003, saying that Roche’s Tecentriq comparator arm restricted enrolment to patients expressing PD-L1 at 50% or above, in line with Tecentriq’s monotherapy label.
Because Keytruda is approved in PD-L1 ≥1% expressers, and comprises the comparator in Keyvibe-003, Merck can test its Tigit combo in the broader population. “It may be easier to detect a combination effect in lower biomarker positives rather than at the higher level, where the PD-1s are pretty effective by themselves,” said Mr Rubin.
He added that in single-arm NSCLC trials “we saw a nice effect” in 1-49% PD-L1 expressers, where Roche notably did not see efficacy in the mid-stage Cityscape trial. A third player, Beigene, is studying its Tigit ociperlimab plus tislelizumab versus Keytruda in the PD-L1 ≥50% population in the Advantig-302 trial, its chief medical officer, Mark Lanasa, told Vantage.
Thus at least Roche has some clinical rationale for continuing to pursue Tigit blockade in NSCLC.
Not so in SCLC. After Dr Rudin’s presentation the Asco discussant, Penn State Cancer Institute’s Dr Chandra Prakash, slated Skyscraper-02 for being a phase 3 study designed solely on the basis of preclinical findings, with “no evidence of clinical activity in SCLC”.
Source: Dr Charles Rudin & Asco.
Asco 2022 – Carvykti casts a long shadow
For Arcellx investors, who backed the group’s audacious $124m flotation in February, in the middle of a biotech slump, Asco was a key test. Judging by today’s data for the group’s lead Car-T project the enthusiasm was not entirely misplaced.
Arcellx was not the only company with Car-T data in multiple myeloma at Asco. Today also featured oral presentations on Gracell’s fast-manufactured dual-acting project and on a novel follow-on approach from the venture capital-backed Chinese group Oricell. As impressive as many of these data are, however, Johnson & Johnson’s Carvykti casts a long shadow.
Indeed, Carvykti’s Cartitude-1 trial, on the basis of which this anti-BCMA Car-T therapy was approved in fifth-line multiple myeloma, seems insurmountable on efficacy: response rate was 98%, including a 78% rate of complete responses. On a cross-trial basis this beat the other two approved BCMA-directed products, Bristol Myers Squibb’s Abecma and GSK’s Blenrep.
And yesterday’s Asco update of Cartitude-1 reported PFS and OS rates, at 28 months’ follow-up, of 55% and 70% respectively. The big chink in the armour of all three approved therapies is toxicity; Carvykti carries a black box warning of cytokine release, neurotoxicity, macrophage-activation syndrome, Parkinsonism – of which one new case has been seen in Cartitude-1 – and Guillain-Barré syndrome.
Arcellx
Perhaps this is where Arcellx comes in. Dr Matthew Frigault, of Massachusetts General Hospital, reported just one case of grade 3 cytokine release, and two grade 3 neurotoxicities, among 31 multiple myeloma patients given CART-ddBCMA.
As for efficacy, all 31 patients went into remission, with a 71% complete response rate, though there were nine relapses by the May 3 data cutoff. CART-ddBCMA has “best-in-class potential”, Rami Elghandour, Arcellx’s chief executive, told Evaluate Vantage.
He highlighted CART-ddBCMA’s activity in extramedullary disease, a negative prognostic factor, claiming: “We’re largely achieving very similar result to [Carvykti], in a much harder to treat patient population, with arguably a very attractive safety profile.”
In terms of design, what makes CART-ddBCMA different is its use of a synthetic binding region instead of an antibody-derived one; this, says Mr Elghandour, results in more transduced cells being Car-positive than with Carvykti, so the cell dose can be lower. And he cites reduced tonic signalling, meaning that the Car-T cells remain relatively fresh.
Interestingly, CART-ddBCMA is being positioned as a product in its own right rather than as a test of this technology, and Arcellx has designed a pivotal study, to start by the year end, in a similar population to Cartitude-1. The BCMA market can support multiple players, Mr Elghandour insists.
Source: Dr Matthew Frigault & Asco.
If so this is good news for Gracell, which is touting a fast-manufactured multiple myeloma Car-T asset that targets CD19 as well as BCMA, in an attempt to counteract BCMA antigen-negative relapse.
This project, GC012F, has generated an 83% ORR among 28 patients, and all 27 patients evaluable for MRD status were negative; 87.5% of eight patients evaluable at 12 months remained MRD-negative. The longest ongoing responses are over 29 months out, Dr Juan Du, of Shanghai Chang Zheng Hospital, told Asco today.
Perhaps in this small population Gracell can make a case for this dual antigen targeting approach. CD19 might seem an unusual second antigen to hit in multiple myeloma, but a 2015 NEJM paper famously described a case report of a multiple myeloma patient who went into sustained complete remission after getting Kymriah, despite lacking CD19 on most malignant cells. It was hypothesised that the remission was brought about because Kymriah targeted rare, CD19-expressing myeloma precursor cells.
Novel antigen
It was Oricell that brought to Asco data on a novel antigen, specifically GPRC5D, which is hit by its Car-T project OriCAR017.
Its study enrols patients with GPRC5D expression on at least 20% of their multiple myeloma cells, 10 of whom appear at an April 30 data cut. All 10 are reported to have gone into remission (six complete responses) across three doses; five of the patients had relapsed on BCMA-targeted Car-T cell therapy.
Still, there is already competition building here, too. Johnson & Johnson’s bispecific talquetamab is probably the most advanced GPRC5D-targeting agent, and posted impressive data at Ash 2020. In 50 evaluable subjects given over 20µg/kg the ORR was 66%, and in the 13 who had received 405µg/kg subcutaneously, which has been set as the phase II dose, ORR was 69%.
While Oricell remains a little-known private Chinese group, Arcellx is basking in its status as a newly minted listed biotech. “Good companies, even in difficult times, are able to go public and are able to fund raise,” said Mr Elghandour. “I think I’d rather be public than private.”
https://www.evaluate.com/vantage/articles/events/conferences/asco-2022-carvykti-casts-long-shadow
Asco 2022 – Merus gets some competition
First, the good news for Merus: its Her2/Her3-targeting bispecific, zenocutuzumab, looks just as good, if not slightly better, than it did a year ago. And the group is hopeful that data presented at Asco today, in NRG1-fusion driven cancers, will help support a tumour-agnostic filing towards the end of this year or early 2023.
Now for the not so good news: a rival project from Elevation Oncology has produced similar overall response rates, albeit in a small number of patients so far. In a tiny niche like NRG1 fusions, competition could be a big deal.
Elevation will present early results on its project, the Her3-targeting MAb seribantumab, at Asco on Tuesday, but it has already detailed the full dataset via press release, a spokesperson told Evaluate Vantage.
| Cross-trial comparison of zenocutuzumab & seribantumab | ||||
|---|---|---|---|---|
| Zenocutuzumab: Enrgy & Early Access Program | Seribantumab: Crestone | |||
| Asco 2021 presentation | Asco 2022 presentation | Asco 2022 presentation | ||
| Cutoff | Apr 13, 2021 | April 12, 2022 | April 18, 2022 | |
| ORR – overall | 31% (14/45)* | 34% (27/79) | 33% (4/12)** | |
| ORR – pancreatic cancer | 42% (5/12) | 42% (8/19) | 0% (0/1) | |
| ORR – NSCLC | 29% (7/24)* | 35% (16/46) | 36% (4/11)** | |
| ORR – other solid tumours | 22% (2/9) | 18% (3/17) | N/A | |
| *Included one PR confirmed after cutoff date; **Includes 2 CRs. Source: Asco & company releases. | ||||
The seribantumab results call into question something that Merus has long maintained: that its dual approach, docking onto Her2 and then blocking Her3, could be more potent than monoclonal antibodies (Asco 2021 – Merus’s slight improvement might not win over investors, June 4, 2021).
However, Merus’s chief executive, Bill Lundberg, maintained this claim when Evaluate Vantage spoke to him on the sidelines of Asco. “We think we have the potential not only to be first in class, but potentially best in class in this setting.”
He noted that patients in Merus’s Enrgy trial and early-access programme received a median of two prior therapies, compared with a median of one in Elevation’s Crestone trial. This raises the possibility that patients in Crestone were less sick, which could have flattered seribantumab’s performance.
And Mr Lundberg added: “We're a couple of years ahead.”
Small market
In NRG1 fusion cancers this head start could make a difference. Merus currently estimates that 0.5-1.5% of pancreatic cancer and 0.3-3% of lung cancer patients have NRG1 fusions, but Mr Lundberg noted these numbers are based partly on epidemiologic studies using old sequencing methods.
“We think the numbers could increase over time with better diagnosis,” he said. “But it's not going to dramatically be tenfold higher. We think it’s several thousand patients per year in the US.”
For now, Merus is not saying how many patients it will need for a US filing, only that it has reached agreement on this with the FDA. “And we believe we'll have sufficient patients with sufficient clinical follow-up around the middle of this year.”
It is not clear yet whether this could support an accelerated or full approval; Mr Lundberg said this would be up to the FDA. The group is currently considering whether to go it alone or sell zenocutuzumab via a partner, assuming it does get the nod.
Competition
Still, Mr Lundberg admitted that the anti-Her3 space is getting crowded. As well as Elevation, Hummingbird Bioscience’s HMBD-001 recently went into the clinic in Her3-positive solid tumours, including NRG1 fusion-driven cancers.
Meanwhile, Aveo Oncology still has hopes of reviving AV-203, despite it being ditched by two partners: Biogen in 2014 and China’s Canbridge in 2021. Aveo is also developing a Her3-targeting antibody radio-conjugate alongside Actinium.
GSK’s GSK2849330 has also produced intriguing results in NRG1 fusion cancers, but is not currently listed on the company’s pipeline.
And Daiichi’s Her3-targeting antibody-drug conjugate patritumab deruxtecan produced encouraging results in breast and lung cancers at Asco, but the company does not appear to be focusing on NRG1 fusions.
Merus will need to keep its first-mover advantage if it wants to make the most of this niche.
| Her3-targeting projects with potential in NRG1 fusion cancers | |||
|---|---|---|---|
| Project | Company | Description | Details |
| Zenocutuzumab | Merus | Anti-Her2/Her3 bispecific | Filing due late 2022/early 2023 based on ph1/2 Enrgy & EAP |
| Seribantumab | Elevation Oncology | Anti-Her3 MAb | Early data from ph1/2 Crestone at Asco 2022; trial could be basis for AA |
| HMBD-001 | Hummingbird Bioscience | Anti-Her3 MAb | First pt dosed in ph1/2* in Dec 2021 |
| GSK2849330 | GSK | Anti-Her3 MAb | Ph1 completed 2017, one of two NRG1 fusion pts had partial response |
| AV-203 | Aveo Oncology | Anti-Her3 MAb | Ph1 completed 2014, one of two NRG1 fusion pts had a partial response |
| *Investigator-sponsored, study enrols pts with Her3-expressing tumours, including NRG1 fusion pts. AA=Accelerated approval; EAP=Early access programme. Source: Evaluate Pharma & clinicaltrials.gov. https://www.evaluate.com/vantage/articles/events/conferences/asco-2022-merus-gets-some-competition | |||
Alkermes Plants Oncology Flag at ASCO
Well-known for its neurological drug development programs, Alkermes has firmly planted its flag as an oncology company at the American Society of Clinical Oncology (ASCO)’s annual meeting. The Ireland-based company presented data from its ARTISTRY-1 clinical trial for nemvaleukin alfa immunotherapy that has laid a foundation for the future.
Speaking to BioSpace ahead of the conference, Jessicca Rege, vice president and head of oncology at Alkermes, said the data from the study confirmed the design hypothesis of the Phase I/II ARTISTRY-1 study by demonstrating preferential expansion of CD8+ T cells and NK cells with minimal effect on Tregs. Nemvaleukin alfa is the company's novel, investigational, engineered interleukin-2 (IL-2) variant immunotherapy that is comprised of modified IL-2 and the high-affinity IL-2 alpha receptor chain. Nemvaleukin is designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells through preferential binding to the intermediate-affinity IL-2 receptor complex. Alkermes is investigating nemvaleukin as both a monotherapy and in combination with Merck’s vaunted checkpoint inhibitor, Keytruda.
At ASCO, Rege will, for the first time, share the entirety of the ARTISTRY-1 program. She said the data seen in the study has checked all of the boxes Alkermes was hoping to see. Rege called ARTISTRY-1 a foundational study that supports the continued development of nemvaleukin, particularly as a monotherapy.
Data from ARTISTRY-1 showed that nemvaleukin demonstrated anti-tumor activity with durable responses as a stand-alone treatment for patients with mucosal melanoma and renal cell carcinoma (RCC) whose disease has progressed following treatment with a checkpoint inhibitor. Rege noted that while checkpoint inhibitors have revolutionized immuno-oncology, there are still a large number of patients who do not respond to those therapeutics. Through selective targeting of the IL-2 pathway, nemvaleukin may be able to deliver significant clinical benefit across multiple tumor types, all while mitigating toxicities that are associated with high-dose recombinant-IL-2, she said.
As a monotherapy, data from ARTISTRY-1 showed that in patients with advanced melanoma or renal cell carcinoma, treatment with nemvaleukin generated a partial response in six patients and stable disease in 31 patients. All melanoma patients who achieved a partial response with nemvaleukin monotherapy had previously progressed on treatment with a checkpoint inhibitor. Of the six evaluable mucosal melanoma patients, two patients achieved a partial response, including one confirmed response. One of those patients has been receiving nemvaleukin monotherapy for more than two years, achieving a duration of response of 79 weeks.
In RCC, of 22 evaluable patients, four achieved a partial response, three of which were confirmed. All renal cell carcinoma patients who achieved a partial response with nemvaleukin monotherapy had previously progressed on treatment with a checkpoint inhibitor.
Rege said that data from ARTISTRY-1 provided the company with important information regarding nemvaleukin's pharmacokinetic and pharmacodynamic profile. Nemvaleukin earned Fast Track designation as well as Orphan Drug designation from the U.S. Food and Drug Administration for mucosal melanoma.
Nemvaleukin is also being assessed in combination with Keytruda (pembrolizumab) through a collaboration forged with Merck last year in the ARTISTRY-7 study.
Data from the ongoing ARTISTRY-1 program showed that out of the 137 patients who were evaluable by the ASCO cutoff date, four showed a complete response and 18 saw a partial response. Stable disease was seen in 60 patients and the overall median duration of response was 23 weeks. Both of the complete responses and two of the partial responses were in patients with platinum-resistant ovarian cancer (PROC). Median duration of response for PROC was 53 weeks. The primary endpoint of ARTISTRY-7 is progression-free survival.
Last year, FDA awarded Fast Track designation to the combination of nemvaleukin and Keytruda for the treatment of PROC.
Rege noted that there is a “synergistic effect” between checkpoint inhibitors and nemvaleukin.
Expressing excitement for the results seen in ARTISTRY-1 and what the future holds for Alkermes’ oncology pipeline, Rege called the data Alkermes’ foundational element. The company is pushing forward with other ARTISTRY clinical programs, including the ARTISTRY-7 Phase III study in PROC, as well as ARTISTRY-3, a study assessing intravenous dosing of nemvaleukin as a monotherapy in multiple solid tumors and ARTISTRY-2, which is assessing subcutaneous dosing of nemvaleukin.
“Alkermes is not known for oncology. We’re coming into the space with a nice foundational building block and building a great portfolio,” she said.
Rege joined Alkermes two years ago when the company was kick-starting its oncology pipeline. When she joined as head of oncology, Rege said she came in with a mindset that although the science can be exciting, they ultimately serve the patient who receives the medication. For many of them, the need for treatment is a matter of life and death. Pointing at the ARTISTRY-1 data, Rege reiterated that this is the foundation that will lead Alkermes’ oncology program into the future.
“When we’re talking about cancer, we have a sense of urgency. At Alkermes, we’ve done well with this sense. In order to get the maximum potential, we have to be focused,” she said. “It’s great when we can offer another birthday, another graduation or the chance to meet a grandchild to these patients. I try to remind my team that we are the voice of the patients. Cancer has impacted so many people, even us. Everything we can do to move these drugs forward is critical.”
https://www.biospace.com/article/alkermes-plants-oncology-flag-at-asco-22/
ImmunityBio Bladder, Pancreatic Cancer Results at ASCO
Data from trials underscore ImmunityBio’s vision of activating NK cells and T cells to advance care in difficult-to-treat cancers
Bladder Cancer: 71% of BCG-unresponsive NMIBC patients who had failed on previous therapies showed a complete response with a median duration of 26.6 months; cystectomy avoidance rate of 91% and 100% bladder cancer overall survival at 24 months with 0% immune-related serious adverse events (SAE)
Advanced Metastatic Pancreatic Cancer: Nant Vaccine more than doubled median overall survival for patients versus historical overall survival with median overall survival in patients with third- to sixth-line pancreatic cancer at 6.2 months and treatment-related SAEs uncommon (6%)
GSK's measles prevention vaccine gets U.S. approval
British drugmaker GSK
"We're proud to make Priorix available in the U.S. for the first time, adding a choice for providers to help protect patients against these highly-contagious diseases," GSK Head of U.S. Vaccines Judy Stewart said.
https://www.nasdaq.com/articles/gsks-measles-prevention-vaccine-gets-u.s.-approval
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